This randomised, placebo-controlled, double-blind trial investigated the safety and effectiveness of unopposed, very-low-dose estradiol for preventing bone loss in a group of post-menopausal women, aged 60-80 years with intact uteri and bone mineral density (BMD) z scores of -2.0 or higher. The women were randomised to receive either 0.014mg of unopposed transdermal estradiol daily or a placebo. Both groups of women received calcium and vitamin supplementation. Lumbar spine and total hip BMD change was measured by dual-energy X-ray absorptiometry and endometrial hyperplasia incidence was assessed by endometrial biopsy. Overall, the findings showed that there was an increase in median plasma estradiol in the estradiol group compared to no change in the placebo group. A greater increase in lumbar spine BMD and an increase in mean total hip BMD for the estradiol group was observed in comparison to the placebo group. In addition, osteocalcin levels and bone-specific alkaline phosphatase were lower in the estradiol group, and endometrial hyperplasia developed in one participant from the estradiol group compared to zero in the placebo group.